Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor, erbB, in the pathophysiology of schizophrenia. Among NRG 1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in modulation of N-methyl-D-aspartate (NMDA) receptor signaling. We have recently examined the expression and transduction of the NRG1- erbB4 mechanism in the postmortem brains of schizophrenia and control subjects. Using a novel postmortem tissue stimulation approach, we found striking alterations of NRG1- erbB4 signaling in the prefrental cortex of schizophrenia subjects. First, NRG1-induced erbB4 activation, measured by tyrosine phosphorylation of erbB4 and its association with PSD-95, was dramatically enhanced, while the expression levels of NRG1 or erbB4 were not altered. Second, the association of erbB4 with PSD-95 and NMDAR as well as PSD-95's coupling with NMDAR were also significantly altered in schizophrenia. Third, NRG1 stimulation attenuates NMDAR activation in the human prefrontal cortex as shown in rodents. NMDAR activation, measured by tyrosine phosphorylation of the receptors, was significantly attenuated in schizophrenia subjects, which we believe to be the first direct demonstration of NMDAR hypofunction in the brains of patients. Finally, when the brain tissues were co-stimulated with NMDA and NRG1, NRG1 induced NMDA attenuation was even greater in schizophrenia subjects, suggesting that the dyregulated NRG1 -erbB4 signaling in schizophrenia may contribute to NMDAR hypofunction. Our central hypothesis is that altered erbB4 signaling in schizophrenia is associated with altered protein -protein interactions in the PSD, including NMDAR complexes. The aims of this proposal are designed to test a model in which altered erbB4 - postsynaptic density (PSD) protein association in schizophrenia leads to enhanced erbB4 signaling, which in turn results in NMDAR hypofunction. By doing so, we will be able to explore whether dysregulated protein - protein interactions in the PSD is a pathophysiologic mechanism for schizophrenia. Aim 1 will first assess whether hyperactive erbB4 signaling is brain region- or ligand-specific in schizophrenia. Aim 2 will specifically address protein protein interactions among erbB4 and other PSD proteins. Aim 3, will further characterize the impact of erbB4 dysregulation on NMDAR signaling and explore possible mechanisms.